N-heterocyclic carbene-catalyzed synthesis of 2-aryl indoles
Transition metal-free catalytic methods for access to 2-arylindole compounds.
1. A method of preparing a 2-arylindole compound, said method comprising:
providing a reaction medium comprising an N-heterocyclic carbene catalyst precursor compound, a base component and an o-aminobenzyl chloride compound of a formula
wherein R 1 is selected from H, halo, cyano, alkyl, haloalkyl and alkoxy moieties; R 2 is selected from H and alkyl moieties; and R 3 is selected from H and amino-protecting groups;
introducing an arylaldehyde compound of a formula ArC(O)H to said reaction medium, wherein Ar is selected from aryl and heteroaryl moieties, where a said heteroatom is selected from S and N, said Ar moiety optionally substituted with one or more halo, cyano, alkyl, haloalkyl, alkoxy acetamido or acetamidoalkoxy groups and combinations thereof, to provide a benzylic ketone intermediate compound; and
introducing an acid component to said reaction medium to promote intramolecular N—C bond formation and dehydration, to provide a 2-arylindole compound of a formula
2. The method of claim 1 wherein said base component is a non-nucleophilic carbonate.
3. The method of claim 1 wherein said carbene catalyst precursor compound is selected from azolium and thiazolium compounds.
4. The method of claim 3 wherein said carbene catalyst precursor compound is 3-(2,6-diethylphenyl)-4,5-dimethylthiazol-3-ium perchlorate.
5. The method of claim 4 wherein said base component is cesium carbonate.
6. The method of claim 1 wherein said arylaldehyde is benzaldehyde and provided by benzoin hydrolysis.
7. The method of claim 1 wherein Ar is selected from phenyl, naphthyl, thiophenyl and pyridyl moieties.
8. A method of preparing a 2-arylindole compound, said method comprising:
providing a reaction medium comprising a thiazol-3-ium carbene catalyst precursor compound, a non-nucleophilic base component and an o-aminobenzyl chloride compound of a formula
wherein R 1 is selected from H, halo, cyano, alkyl, haloalkyl and alkoxy moieties; R 2 is selected from H and alkyl moieties; and R 3 is selected from H and amino-protecting groups;
introducing 1,4-dioxane and an arylaldehyde compound of a formula ArC(O)H to said reaction medium, wherein Ar is selected from aryl and heteroaryl moieties, where a said heteroatom is selected from S and N, said Ar moiety optionally substituted with one or more halo, cyano, alkyl, haloalkyl, alkoxy, acetamido or acetamidoalkoxy groups and combinations thereof; and
introducing an acid component to said reaction medium to promote intramolecular N—C bond formation and dehydration, to provide a 2-arylindole compound of a formula
said method in a single reaction vessel absent intermediate isolation and absent transfer of reaction medium.
9. The method of claim 8 wherein said non-nucleophilic base component is a carbonate.
10. The method of claim 8 wherein said carbene catalyst precursor compound is 3-(2,6-diethylphenyl)-4,5-dimethylthiazol-3-ium perchlorate.
11. The method of claim 10 wherein said non-nucleophilic base component is cesium carbonate.
12. The method of claim 8 wherein said arylaldehyde is benzaldehyde and provided by benzoin hydrolysis.
13. A method of preparing a 2-arylindole compound, said method comprising:
providing a reaction medium comprising a thiazol-3-ium carbene catalyst precursor compound, a non-nucleophilic base component and an o-aminobenzyl chloride compound of a formula
wherein R 1 is selected from H, halo, cyano, alkyl, haloalkyl and alkoxy moieties; R 2 is selected from H and alkyl moieties; and R 3 is selected from H and amino-protecting groups, 1,4-dioxane and an arylaldehyde compound of a formula ArC(O)H, wherein Ar is selected from phenyl, naphthyl, thiophenyl and pyridyl moieties, said Ar moiety optionally substituted with one or more halo, cyano, alkyl, haloalkyl, alkoxy, acetamido or acetamidoalkoxy groups and combinations thereof; and
introducing an acid component to said reaction medium to promote intramolecular N—C bond formation and dehydration, to provide a 2-arylindole compound of a formula
said method in a single reaction vessel absent intermediate isolation and absent transfer of reaction medium.
14. The method of claim 13 wherein said non-nucleophilic base component is a carbonate.
15. The method of claim 13 wherein said carbene catalyst precursor compound is 3-(2,6-diethylphenyl)-4,5-dimethylthiazol-3-ium perchlorate.
16. The method of claim 15 wherein said non-nucleophilic base component is cesium carbonate.
17. The method of claim 16 wherein said arylaldehyde is N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(4-formylphenoxyl)acetamide.
18. The method of claim 13 wherein said arylaldehyde is benzaldehyde and provided by benzoin hydrolysis.
19. A method of using an N-heterocyclic carbene catalyst to prepare a 2-arylindole compound, said method comprising:
providing a reaction medium comprising a thiazol-3-ium carbene catalyst precursor compound, a non-nucleophilic base component and an o-aminobenzyl chloride compound of a formula
wherein R 1 is selected from H, halo, cyano, alkyl, haloalkyl and alkoxy moieties; R 2 is selected from H and alkyl moieties; and R 3 is selected from H and amino-protecting groups, 1,4-dioxane and an arylaldehyde compound of a formula ArC(O)H, wherein Ar is selected from aryl and heteroaryl moieties, where a said heteroatom is selected from S and N, said Ar moiety optionally substituted with one or more halo, cyano, alkyl, haloalkyl, alkoxy, acetamido or acetamidoalkoxy groups and combinations thereof;
generating an acylanion component from said carbene catalyst precursor compound in said reaction medium; and
introducing an acid component to said reaction medium to promote intramolecular N—C bond formation and dehydration, to provide a 2-arylindole compound of a formula
said method in a single reaction vessel absent intermediate isolation and absent transfer of reaction medium.
20. The method of claim 19 wherein said non-nucleophilic base component is a carbonate.
21. The method of claim 19 wherein said carbene catalyst precursor compound is 3-(2,6-diethylphenyl)-4,5-dimethylthiazol-3-ium perchlorate.
22. The method of claim 21 wherein said base component is cesium carbonate.
23. The method of claim 22 wherein said arylaldehyde is N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(4-formylphenoxyl)acetamide.
24. The method of claim 19 wherein said arylaldehyde is benzaldehyde and provided by benzoin hydrolysis.
25. A compound of a formula
wherein each of R 1 and R 2 is H, R 3 is selected from H and amino-protecting groups and Ar is a 3,4-dibromophenyl moiety.